PROJECT SUMMARY Despite evidence from human and animal studies that clearly identifies neurotoxicity as the primary adverse endpoint, the long-term effects of repeated occupational and environmental exposures to organophosphorus pesticides (OPs) remain poorly understood. There is also a critical need to investigate the susceptibility of children and adolescents to pesticides, since the developing brain may be uniquely sensitive to the neurotoxic effects of these agents. Partnering with colleagues at Egypt's Menoufia University, we conducted a pilot study of adolescents working for the Ministry of Agriculture as pesticide applicators for the cotton crop. Building on these preliminary findings, we propose a longitudinal study to investigate the relationship between sensitive and specific biomarkers of pesticide exposure, effect and susceptibility and multiple measures of neurobehavioral function in this unique cohort over a 5 year period to assess cumulative and potentially reversible effects. Our overarching hypothesis is that the inherent plasticity of the developing adolescent brain will allow recovery from selected neurobehavioral deficits associated with short- and long-term exposures to pesticides. Three aims address this hypothesis, expand on the successful efforts begun in the R21 project, to build research skills at Menoufia and work with the Ministry of Agriculture to identify susceptible populations and put into place appropriate measures to reduce pesticide exposure. Aim 1 will determine the association between pesticide exposure and neurobehavioral function in a longitudinal study among adolescent cohorts with occupational (applicators) or environmental (non-applicators) exposures to test the hypothesis that neurobehavioral performance deficits associated with short-term exposure occur during the application season but that there is recovery of selected neurobehavioral functional domains after the summer spray season ends. Some deficits may persist beyond the spray season or after repeated summer spray seasons. A biologically- based exposure assessment will incorporate levels of urinary metabolites of chlorpyrifos and profenophos (OPs) and alpha-cypermethrin (pyrethroid) and functional polymorphisms in key enzymes involved in OP metabolism (CYP2B6, CYP2C19, and PON1) as modifiers of bioeffective dose. Aim 2 will expand the research capacity at Menoufia University by establishing a Research Institute that will: (a), build epidemiologic research capacity (b) teach grant writing and research skills in short courses held locally and through videoconferences, (c) provide mentoring and international education experiences, and (d) implement a pilot project research program. This is designed to create a competitive research culture at Menoufia University. Aim 3 will develop a training program for the Ministry of Agriculture workers (including applicators) on ways to reduce exposure through hygiene, behavior (work practice) change and use of protective equipment, addressing both environmental (home) and occupational exposures. A randomized controlled trial design will evaluate the impact of the training program on reaction, behavior, and knowledge (learning and retention).